The overall goal of this application is to determine the role of the autonomic nervous system in the abnormalities associated with Chronic Fatigue Syndrome. We propose to test the hypothesis that the sympathetic nervous system contributes to the cardiovascular and inflammatory abnormalities present in the Chronic Fatigue Syndrome (CFS) and, in particular in the subset of patients characterized by postural tachycardia (POTS). CFS and POTS are seen mostly in otherwise normal young women, and are the cause of significant disability. Our preliminary indicates a decrease in plasma volume in patients with POTS, which can contribute to, and be the consequence of, sympathetic activation. Our preliminary studies also indicate an interaction between the sympathetic nervous system and nitric oxide mechanisms; this may also create a negative feedback mechanism whereby a decrease nitric oxide results in sympathetic activation, and increased sympathetic activity results in impaired nitric oxide mechanisms. We have developed a paradigm that will allow us to define selectively the contribution of endothelial nitric oxide to blood pressure regulation and will apply this approach to patients with CFS and POTS. In addition, our preliminary studies indicate that sympathetic activity is associated with inflammatory processes. In particular, C-reactive protein are increased in patients with POTS and, conversely, decreased in patients with low sympathetic tone due to pure autonomic unsuccessful undertaking. We propose to measure validated indices of sympathetic activity, inflammation and oxidative stress in patients with CFS and POTS, and compare them to appropriate control groups, including patients with CFS without POTS, POTS without CFS, and normal controls. If our hypothesis is correct, and sympathetic activity contributes to the pathophysiology of CFS, then chronic inhibition of sympathetic tone will result in improvement of symptoms, cardiovascular alterations, volume defects, and inflammatory abnormalities present in CFS. [unreadable] [unreadable] [unreadable]